Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

Abstract

1 The biosynthesis of endothelin-1 is increased in the diabetic state. So this peptide may cause diabetic vascular complications. We tested this possibility by chronically administering J-104132, a potent orally active mixed antagonist of endothelin A and B (ET A /ET B ) receptors to streptozotocin (STZ)-induced diabetic rats and focusing on changes in endothelial function. 2 The acetylcholine (ACh)-induced endothelium-dependent relaxation was impaired in diabetic rats and this impairment was signi®cantly attenuated following chronic administration of J-104132 (10 mg kg 71 , p.o., daily for 4 weeks).3 In an in vitro experiment using aortae from diabetic rats, the ACh-induced relaxation was not changed by the presence of J-104132 (3610 79 M). 4 The expression levels of the mRNA for endothelial nitric oxide synthase was comparable among aortae from the three groups (control, diabetic and chronically J-104132-treated diabetic). 5 The amount of superoxide anion was signi®cantly greater in aortae from diabetic rats than in controls. Chronic J-104132 treatment signi®cantly decreased the level of superoxide anion in diabetic rats. 6 The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was signi®cantly increased in STZ-induced diabetic rats and this increase was completely prevented by chronic administration of J-104132. 7 These results suggest that in STZ-induced diabetic rats, ET-1 may be directly involved in impairing endothelium-dependent relaxation via increased superoxide-anion production.

Effects of Chronic Administration of Fruit Extract (Citrus unshiu MARC) on Endothelial Dysfunction in Streptozotocin-Induced Diabetic Rats

“…Blood Glucose and Animal Body Weights As reported previously, 7,11,12) at the time of the experiment all STZ-treated rats exhibited hyperglycemia, their blood glucose concentrations being significantly higher than those of the agematched nondiabetic control rats (Table 1). Moreover, the body weights of the diabetic rats were significantly lower than those of the age-matched control rats at the time of the experiment ( Table 1).…”

“…We previously reported that acetylcholine (ACh)-induced endothelium-dependent relaxation was impaired in the aorta at 10-12 weeks after streptozotocin (STZ) injection (which creates a model of Type 1 diabetes). 7,11,12) Here, to investigate the possible effect of Citrus unshiu MARC extract we started chronic treatment with this extract immediately after the STZ injection, and continued it for 10 weeks.…”

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

“…In addition, ET-1 (a vasoconstrictor peptide secreted from endothelial cell) is thought to play a pathological role in a number of vascular diseases (Goto et al, 1996). Interestingly, it was recently reported that ET-1 can activate PI3-K in several cells (Ishibashi et al, 2000;Kawanabe et al, 2003) and that ET-1 activates NAD(P)H oxidase and induces superoxide production in cultured endothelial and smooth muscle cells (Duerrschmidt et al, 2000;Wedgwood et al, NAD(P)H oxidase is increased in STZ-induced diabetic aortae (Kanie and Kamata, 2002) and that this increase is normalized by the endothelin antagonist, J-104132, suggesting that ET-1 is involved in the increased formation of superoxide anions. Furthermore, we found that chronic administration of a relatively low dose of bezafibrate, which was insufficient to alter the levels of plasma lipids (including total cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride), exerted an improvement effect on the endothelial dysfunction seen in the aorta in rats with established STZ-induced diabetes.…”

Relationships among ET-1, PPAR.GAMMA., oxidative stress and endothelial dysfunction in diabetic animals

“…A perturbation of the balance between ETA-and ETBreceptor activities may contribute to the pathogenesis of vascular disease (Brunner et al, 2006;Goto et al, 1996;Kanie and Kamata, 2002;Matsumoto et al, 2004c;Miyauchi and Masaki, 1999). Some, but not all, experimental models of hypertension, atherosclerosis, and diabetes display high levels of circulating ET-1, and exhibit endothelial dysfunction (Barton et al, 1998;Brunner et al, 2006;Kanie et al, 2003;Makino and Kamata, 1998).…”

“…Moreover, we recently studied the relationship among the ET-1 system, endothelium-dependent relaxation, and chronic pioglitazone treatment using aortas from STZ-induced diabetic rats (Matsumoto et al, 2007d). In such animals, we previously reported that: (1) the plasma ET-1 level is increased and that this increase may be due to an overexpression of the mRNA for prepro-ET-1 (Makino and Kamata, 1998;Makino et al, 2001), (2) the overproduction of ET-1 seen in STZ-induced diabetes results from the hyperglycemia, not from any increase in either LDL cholesterol or triglyceride (Makino and Kamata, 2000), (3) the expression of the mRNA for p22phox is increased in STZinduced diabetes, an increase that is completely preventable by the chronic administration of J-104132 (a potent, orally active, mixed antagonist of ETA and ETB receptors) (Kanie and Kamata, 2002), and (4) short-term or prolonged treatment with ET-1 impairs endothelial function in the aorta both in nondiabetic rats Matsumoto et al, 2007d) and in rats with established STZ-induced diabetes . Moreover, we have demonstrated that chronic administration of the PPARα agonist bezafibrate to established STZ-induced diabetic rats normalizes both the mRNA for prepro-ET-1 and the plasma concentration of ET-1, while improving endothelium-dependent relaxation (Kanie et al, 2003).…”